Post-surgery adjuvant therapy produces changes in cognitive function in up to 70% women with breast cancer. Our recent work demonstrates that breast cancer patients receiving adjuvant hormonal treatment also exhibit a decline in cognition three months post treatment, providing new evidence that MCI also arises from hormonal therapy. To date, no investigation has assessed the neural correlates of adjuvant hormonal therapy, nor have any studies determined how to identify individuals at risk for treatment-related cognitive impairment. We propose to use longitudinal magnetic resonance imaging (MRI) to identify predictors and mechanisms of cognitive impairment in breast cancer patients receiving hormonal treatment. We will achieve this by using structural and functional assessments that are sensitive to the integrity of the hippocampal-cortical circuitry. Our central hypothesis is tha measures of the hippocampal-cortical circuitry can be used to predict cognitive decline, and that the trajectories of specific domains of cognitive performance in patients receiving adjuvant therapy may be related to trajectories of specific hippocampal-cortical circuitry components. Aims: I. To determine treatment-related cognitive impairment. We will determine different trajectories of cognition over time by analyzing neuropsychological measures at all time points using growth mixture modeling. II. Using baseline hippocampal-cortical circuitry markers to predict treatment-related cognitive impairment at follow-up. We will assess the predictability of structural and functional markers and test that integration of measures of structure and function will provide greater sensitivity to predict cognitive impairment. III. Using longitudinal hippocampal-cortical circuitry markers to determine the neuro-pathophysiology of treatment-related cognitive impairment. We will test for relationships between circuitry structure and function in order to identify and characterize patterns linked to treatment- related cognitive decline. We will test the specificity of structural and functional changes in the circuitry components that are associated with domains of cognitive impairment and trajectories of cognitive decline. IV. To integrate research and clinical data to augment patient care, and to establish longitudinal neuroimaging database. PUBLIC HEALTH RELEVANCE: Early detection of treatment-related MCI prior to the development of clinical symptoms will fill key knowledge gaps regarding the underlying neural mechanisms, and will build a foundation for future interventional studies. This knowledge could be refined in future studies in order to develop clinically useful cognitive and neural prospective markers of MCI at the time of treatment, therefore allowing health care providers to plan appropriate care strategies aimed at improving the quality of life for cancer survivors.